Summary Abstract Pneumonic plague is the deadliest form of disease caused by Yersinia pestis and the basis for its classification as a Tier 1 Select Agent. In the absence of antibiotics, mortality rates approach 100% within a week of inhalation of Y. pestis. The progression of pneumonic plague begins with an extended ?pre-inflammatory? phase, featuring no disease symptoms despite a rapidly increasing number of bacteria in the lung. After 36-48 hours, there is an abrupt switch to a ?pro-inflammatory? phase characterized by the rapid onset of symptoms, the induction of pro-inflammatory cytokines, and the dramatic accumulation of neutrophils in the airways. Progression into the pro-inflammatory phase of disease leads to the severe necrotizing pneumonia that is the hallmark of pneumonic plague, but the factors influencing this biphasic disease progression are poorly defined. The objective of the work proposed here is to characterize the pulmonary factors/conditions that control the onset of inflammation and the neutrophil-related processes that contribute to host damage. The first Aim probes the regulation of inflammation during the pre-inflammatory phase. We have previously shown that virulent Y. pestis triggers early production of a pro-inflammatory cytokine (IL-1?) in the lung, and we have preliminary data suggesting that this is due to simultaneous induction of the IL-1 receptor antagonist (IL-1RA). We will test that theory by selective addition/depletion experiments, coupled with evaluation of the kinetics of neutrophil influx and other parameters of disease progression. The second Aim focuses on neutrophil-mediated damage in the pro-inflammatory phase. We recently reported that depletion of neutrophils prior to pulmonary infection with Y. pestis significantly diminishes inflammatory lung pathology. We will utilize currently available knockout mouse lines to implicate neutrophil-related functions that contribute to the inflammatory damage in the lung. Furthermore, we will use commercially available inhibitors to suppress host innate immune functions and enhance antibiotic efficacy for treating pneumonic plague.